Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras
Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective th...
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/168695 |
| _version_ | 1811692271758737408 |
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| author | Do, Thang Cong Lau, Junwei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jiajia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Do, Thang Cong Lau, Junwei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jiajia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang |
| author_sort | Do, Thang Cong |
| collection | NTU |
| description | Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future. |
| first_indexed | 2024-10-01T06:33:08Z |
| format | Journal Article |
| id | ntu-10356/168695 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:33:08Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1686952023-06-16T15:31:48Z Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras Do, Thang Cong Lau, Junwei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jiajia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang School of Physical and Mathematical Sciences Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences School of Chemistry, Chemical Engineering and Biotechnology Science::Chemistry Chemical Activation Enzymes Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) Published version This work is supported by the Ministry of Education, Singapore (MOE), Tier 1 RG6/20, the Agency for Science, Technology and Research (A*STAR) (grant nos. A1883c0011 and A20E5c0090), awarded at NTU, National Natural Science Foundation of China (NSFC; no. 51929201), National Medical Research Council Singapore Large Collaborative Grant DYNAMO (NMRC/OFLCG/001/2017), and National Medical Research Council Singapore Large Collaborative Grant TAAP (NMRC/OFLCG/004/2018). 2023-06-15T04:44:33Z 2023-06-15T04:44:33Z 2022 Journal Article Do, T. C., Lau, J., Sun, C., Liu, S., Kha, K. T., Lim, S. T., Oon, Y. Y., Kwan, Y. P., Ma, J., Mu, Y., Liu, X., Carney, T. J., Wang, X. & Xing, B. (2022). Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras. Science Advances, 8(50), eabq2216-. https://dx.doi.org/10.1126/sciadv.abq2216 2375-2548 https://hdl.handle.net/10356/168695 10.1126/sciadv.abq2216 36516252 2-s2.0-85144221913 50 8 eabq2216 en RG6/20 A1883c0011 A20E5c0090 NMRC/OFLCG/001/2017 NMRC/OFLCG/004/2018 Science Advances © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). application/pdf |
| spellingShingle | Science::Chemistry Chemical Activation Enzymes Do, Thang Cong Lau, Junwei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jiajia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
| title | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
| title_full | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
| title_fullStr | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
| title_full_unstemmed | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
| title_short | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
| title_sort | hypoxia deactivates epigenetic feedbacks via enzyme derived clicking proteolysis targeting chimeras |
| topic | Science::Chemistry Chemical Activation Enzymes |
| url | https://hdl.handle.net/10356/168695 |
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